Epigenetic mechanisms in amyotrophic lateral sclerosis: A short review

Dolinar, Ana; Ravnik‐Glavač, Metka; Glavač, Damjan

doi:10.1016/j.mad.2018.03.005

Cited by 20 publications

(9 citation statements)

References 86 publications

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“…Dozens of genes and many non-genetic factors, including advanced age, being male, infections, intense physical activity, body mass index, nutritional state, and exposure to environmental factors, such as organophosphates and heavy metals, have been linked to sporadic ALS risk [7,8]. Epigenetic mechanisms, dysregulated either by environmental factors or by the presence of mutations in ALS-causative genes, are increasingly believed to contribute to ALS pathogenesis and progression [9]. Particularly, several studies revealed global and gene-specific epigenetic changes in ALS animal models and in tissues derived from both familial and sporadic ALS patients [10][11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Reduced mitochondrial D-loop methylation levels in sporadic amyotrophic lateral sclerosis

et al. 2020

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Background Mitochondrial dysregulation and aberrant epigenetic mechanisms have been frequently reported in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), and several researchers suggested that epigenetic dysregulation in mitochondrial DNA (mtDNA) could contribute to the neurodegenerative process. We recently screened families with mutations in the major ALS causative genes, namely C9orf72, SOD1, FUS, and TARDBP, observing reduced methylation levels of the mtDNA regulatory region (D-loop) only in peripheral lymphocytes of SOD1 carriers. However, until now no studies investigated the potential role of mtDNA methylation impairment in the sporadic form of ALS, which accounts for the majority of disease cases. The aim of the current study was to investigate the D-loop methylation levels and the mtDNA copy number in sporadic ALS patients and compare them to those observed in healthy controls and in familial ALS patients. Pyrosequencing analysis of D-loop methylation levels and quantitative analysis of mtDNA copy number were performed in peripheral white blood cells from 36 sporadic ALS patients, 51 age- and sex-matched controls, and 27 familial ALS patients with germinal mutations in SOD1 or C9orf72 that represent the major familial ALS forms. Results In the total sample, D-loop methylation levels were significantly lower in ALS patients compared to controls, and a significant inverse correlation between D-loop methylation levels and the mtDNA copy number was observed. Stratification of ALS patients into different subtypes revealed that both SOD1-mutant and sporadic ALS patients showed lower D-loop methylation levels compared to controls, while C9orf72-ALS patients showed similar D-loop methylation levels than controls. In healthy controls, but not in ALS patients, D-loop methylation levels decreased with increasing age at sampling and were higher in males compared to females. Conclusions Present data reveal altered D-loop methylation levels in sporadic ALS and confirm previous evidence of an inverse correlation between D-loop methylation levels and the mtDNA copy number, as well as differences among the major familial ALS subtypes. Overall, present results suggest that D-loop methylation and mitochondrial replication are strictly related to each other and could represent compensatory mechanisms to counteract mitochondrial impairment in sporadic and SOD1-related ALS forms.

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Section: Introductionmentioning

confidence: 99%

Reduced mitochondrial D-loop methylation levels in sporadic amyotrophic lateral sclerosis

et al. 2020

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“…The reason for motor neuron death in other cases remains elusive. Several epigenetic mechanisms have been already implicated in the disease development and progression [7]. Among them are also non-coding RNAs with several distinct groups of molecules—micro RNAs (miRNAs), long non-coding RNAs (lncRNAs), and small nucleolar RNAs (snRNAs) [8].…”

Section: Introductionmentioning

confidence: 99%

Circular RNAs as Potential Blood Biomarkers in Amyotrophic Lateral Sclerosis

et al. 2019

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Circular RNAs (circRNAs) are emerging as a novel, yet powerful player in many human diseases. They are involved in several cellular processes and are becoming a noteworthy type of biomarkers. Among other functions, circRNAs can serve as RNA sponges or as scaffolds for RNA-binding proteins. Here, we investigated a microarray expression profile of circRNAs in leukocyte samples from ALS patients and age- and sex-matched healthy controls to identify differentially expressed circRNAs. We selected 10 of them for a qPCR validation of expression on a larger set of samples, identification of their associations with clinical parameters, and evaluation of their diagnostic potential. In total, expression of 7/10 circRNAs was significant in a larger cohort of ALS patients, compared with age- and sex-matched healthy controls. Three of them (hsa_circ_0023919, hsa_circ_0063411, and hsa_circ_0088036) showed the same regulation as in microarray results. These three circRNAs also had AUC > 0.95, and sensitivity and specificity for the optimal threshold point > 90%, showing their potential for using them as diagnostic biomarkers.

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“…Besides tumors, the main class of diseases associated with epigenetic modifications is neurodegenerative disease (40). The association between DNA methylation and NDD is confirmed in Parkinson's disease (41), Alzheimer's disease (42), amyotrophic lateral sclerosis (43), and multiple sclerosis (44). In these diseases, some of the genes are hypermethylated while others are hypomethylated.…”

Section: Dna Methylationmentioning

confidence: 96%

Memorable Food: Fighting Age-Related Neurodegeneration by Precision Nutrition

et al. 2021

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Healthcare systems worldwide are seriously challenged by a rising prevalence of neurodegenerative diseases (NDDs), which mostly, but not exclusively, affect the ever-growing population of the elderly. The most known neurodegenerative diseases are Alzheimer's (AD) and Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, but some viral infections of the brain and traumatic brain injury may also cause NDD. Typical for NDD are the malfunctioning of neurons and their irreversible loss, which often progress irreversibly to dementia and ultimately to death. Numerous factors are involved in the pathogenesis of NDD: genetic variability, epigenetic changes, extent of oxidative/nitrosative stress, mitochondrial dysfunction, and DNA damage. The complex interplay of all the above-mentioned factors may be a fingerprint of neurodegeneration, with different diseases being affected to different extents by particular factors. There is a voluminous body of evidence showing the benefits of regular exercise to brain health and cognitive functions. Moreover, the importance of a healthy diet, balanced in macro- and micro-nutrients, in preventing neurodegeneration and slowing down a progression to full-blown disease is evident. Individuals affected by NDD almost inevitably have low-grade inflammation and anomalies in lipid metabolism. Metabolic and lipid profiles in NDD can be improved by the Mediterranean diet. Many studies have associated the Mediterranean diet with a decreased risk of dementia and AD, but a cause-and-effect relationship has not been deduced. Studies with caloric restriction showed neuroprotective effects in animal models, but the results in humans are inconsistent. The pathologies of NDD are complex and there is a great inter-individual (epi)genetic variance within any population. Furthermore, the gut microbiome, being deeply involved in nutrient uptake and lipid metabolism, also represents a pillar of the gut microbiome–brain axis and is linked with the pathogenesis of NDD. Numerous studies on the role of different micronutrients (omega-3 fatty acids, bioactive polyphenols from fruit and medicinal plants) in the prevention, prediction, and treatment of NDD have been conducted, but we are still far away from a personalized diet plan for individual NDD patients. For this to be realized, large-scale cohorts that would include the precise monitoring of food intake, mapping of genetic variants, epigenetic data, microbiome studies, and metabolome, lipidome, and transcriptome data are needed.

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Epigenetic mechanisms in amyotrophic lateral sclerosis: A short review

Cited by 20 publications

References 86 publications

Reduced mitochondrial D-loop methylation levels in sporadic amyotrophic lateral sclerosis

Reduced mitochondrial D-loop methylation levels in sporadic amyotrophic lateral sclerosis

Circular RNAs as Potential Blood Biomarkers in Amyotrophic Lateral Sclerosis

Memorable Food: Fighting Age-Related Neurodegeneration by Precision Nutrition

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